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Genotypic and bioinformatic evaluation of the alpha- l -iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru

View Article: PubMed Central - PubMed

ABSTRACT

Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by mutations in the gene encoding the lysosomal enzyme α-l-iduronidase (IDUA), which is instrumental in the hydrolysis of the glycosaminoglycans, dermatan and heparan sulfate. The accumulation of unhydrolyzed glycosaminoglycans leads to pathogenesis in multiple tissue types, especially those of skeletal, nervous, respiratory, cardiovascular, and gastrointestinal origin.

Although molecular diagnostic tools for MPSI have been available since the identification and characterization of the IDUA gene in 1992, Colombia, Ecuador, and Peru have lacked such methodologies. Therefore, the mutational profile of the IDUA gene in these countries has largely been unknown. The goal of this study was to characterize genotypes in 14 patients with MPSI from Colombia, Ecuador, and Peru.

The most common mutation found at a frequency of 42.8% was W402X. Six patients presented with seven novel mutations, a high novel mutational rate in this population (32%). These novel mutations were validated using bioinformatic techniques. A model of the IDUA protein resulting from three of the novel missense mutations (Y625C, P385L, R621L) revealed that these mutations alter accessible surface area values, thereby reducing the accessibility of the enzyme to its substrates.

This is the first characterization of the mutational profile of the IDUA gene in patients with MPSI in Colombia, Ecuador, and Peru. The findings contribute to our understanding of IDUA gene expression and IDUA enzyme function, and may help facilitate early and improved diagnosis and management for patients with MPSI.

No MeSH data available.


Related in: MedlinePlus

Model of splice site alteration in the IVS9+1g>t mutation.Model of the IVS9+1g>t mutation in exon 9 of patient MPSI 008. The guanine (G) to thymine (T) substitution at the donor splice site leads to the loss of recognition of this sequence by the spliceosome, and retention of intron 9.
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f0005: Model of splice site alteration in the IVS9+1g>t mutation.Model of the IVS9+1g>t mutation in exon 9 of patient MPSI 008. The guanine (G) to thymine (T) substitution at the donor splice site leads to the loss of recognition of this sequence by the spliceosome, and retention of intron 9.

Mentions: Sequence and bioinformatic analysis of the splice site mutation IVS9+1g>t allowed further characterization of this mutation. In patients with MPS I who carry this mutation, the guanine residue at the 5′ donor splice site of intron 9 is replaced by a thymine residue. This results in a defective splice site, and preservation of the entire intron 9, as shown in Fig. 1.


Genotypic and bioinformatic evaluation of the alpha- l -iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru
Model of splice site alteration in the IVS9+1g>t mutation.Model of the IVS9+1g>t mutation in exon 9 of patient MPSI 008. The guanine (G) to thymine (T) substitution at the donor splice site leads to the loss of recognition of this sequence by the spliceosome, and retention of intron 9.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121354&req=5

f0005: Model of splice site alteration in the IVS9+1g>t mutation.Model of the IVS9+1g>t mutation in exon 9 of patient MPSI 008. The guanine (G) to thymine (T) substitution at the donor splice site leads to the loss of recognition of this sequence by the spliceosome, and retention of intron 9.
Mentions: Sequence and bioinformatic analysis of the splice site mutation IVS9+1g>t allowed further characterization of this mutation. In patients with MPS I who carry this mutation, the guanine residue at the 5′ donor splice site of intron 9 is replaced by a thymine residue. This results in a defective splice site, and preservation of the entire intron 9, as shown in Fig. 1.

View Article: PubMed Central - PubMed

ABSTRACT

Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by mutations in the gene encoding the lysosomal enzyme α-l-iduronidase (IDUA), which is instrumental in the hydrolysis of the glycosaminoglycans, dermatan and heparan sulfate. The accumulation of unhydrolyzed glycosaminoglycans leads to pathogenesis in multiple tissue types, especially those of skeletal, nervous, respiratory, cardiovascular, and gastrointestinal origin.

Although molecular diagnostic tools for MPSI have been available since the identification and characterization of the IDUA gene in 1992, Colombia, Ecuador, and Peru have lacked such methodologies. Therefore, the mutational profile of the IDUA gene in these countries has largely been unknown. The goal of this study was to characterize genotypes in 14 patients with MPSI from Colombia, Ecuador, and Peru.

The most common mutation found at a frequency of 42.8% was W402X. Six patients presented with seven novel mutations, a high novel mutational rate in this population (32%). These novel mutations were validated using bioinformatic techniques. A model of the IDUA protein resulting from three of the novel missense mutations (Y625C, P385L, R621L) revealed that these mutations alter accessible surface area values, thereby reducing the accessibility of the enzyme to its substrates.

This is the first characterization of the mutational profile of the IDUA gene in patients with MPSI in Colombia, Ecuador, and Peru. The findings contribute to our understanding of IDUA gene expression and IDUA enzyme function, and may help facilitate early and improved diagnosis and management for patients with MPSI.

No MeSH data available.


Related in: MedlinePlus